Macrocytic Anemia
(RX) What are the 4 causes of Folate Deficiency?
1. malnutrition (alcoholics)... 2. malabsorption... 3. drugs... 4. increased requirement (hemolytic anemia, pregnancy)
What are 3 causes of folate deficiency?
1. poor diet... 2. increased demand... 3. folate antagonists
What is the Schilling test?
4-stage test determines if cause of vitamin B12 is due to dietary insufficiency vs malabsorption... the purpose is to determine if the patient has pernicious anemia (intestines cannot absorb enough vitamin B12...decrease in RBCs)
Why is there excessive excretion of orotic acid in urine?
Accumulation of orotic acid results from... 1. inability to convert orotic acid to UMP (de novo pyrimidine synthesis pathway) due to... 2. defect UMP Synthase
(RX) How can you contrast vitamin B12 deficiency-megaloblastic anemia to folate deficiency?
Anemia secondary to insufficient intake may take several years to develop due to liver's ability to store B12... contrast to folate deficiency which is sooner
What is macrocytic anemia?
MCV > 100 um^3... 1 less division of erythroid progenitors due to imparied DNA synthesis... enlarged RBCs...
Refresher... What reaction is Vitamin B12 critical for?
Methylmalonic Acid to Succinyl CoA (fat metabolism)...
(RX) Are there neurological symptoms in Folate Deficiency?
NO, (in contrast to B12 cobalamin deficiency)
How do nonmegaloblastic anemias appear on smear?
RBC macrocytosis WITHOUT hypersegmented neutrophils
(RX) What test historically diagnoses vitamin B12 cobalamin deficiency?
Schilling test
What is cobalamin?
Vitamin B12
What are the pathological findings of pernicious anemia?
chronic atrophic glossitis... decreased production of intrinsic factor subacute combined degeneration
How do patients with Diamond-Black Fan anemia DBA present on hemoglobin electrophoresis?
elevated hemoglobin F... HbF... but decreased total Hb
What are nonmegaloblastic anemias?
macrocytic anemia in which DNA synthesis is unimpaired... causes: alcoholism and liver disease
What is the mode of inheritance of orotic aciduria?
autosomal recessive
What is vitamin B12?
cobalamin
What is Diamond-Black Fan anemia?... When does Diamond Black Fan anemia present?
congenital erythroid aplasia... rapid onset anemia within 1st year of life due to instrinct defect in erythroid progenitor cells
Why is pancreatic insufficiency a cause of vitamin B12 deficiency?
decreased pancreatic protease levels lead to decreased separation of Vitamin B12 from R-binder...ultimately decreased absorption
What are macroovalocytes?
enlarged, oval-shaped erythrocytes (red blood cells
A third type of megaloblastic anemia is orotic aciduria... What is orotic aciduria?
excessive excretion of orotic acid in urine
What cells are absent on smear in nonmegaloblastic anemia, differentiating them from megaloblastic anemia?
hypersegmented neutrophils are absent in nonmegaloblastic anemia
Describe the pathogenesis of megaloblastic anemia?
impaired DNA synthesis... maturation of nucleus of precursor cells in bone marrow delayed relative to maturation of cytoplasm... cytoplasm matures quicker than nucleus
What is a hypersegmented neutrophil (see in megaloblastic anemia)?
neutrophil greater than 5 nuclear lobes... normal has 3-5 lobes
How long does folate deficiency develop?
relatively quickly... within months because body stores are minimal
Damage to terminal ileum leads to Vitamin B12 deficiency. What are 2 causes of damage to terminal iluem?
1. Crohn's Disease... 2. Fish tapeworm = Diphyllobothrium latum
Folate and Vitamin B12 (cobalamin) are required for synthesis of DNA precursors (i.e. pyrimidines like thymidine)... Describe their roles in DNA precursor synthesis?
1. Folate exists in body as methyl tetrahydrofolate...m-THF... 2. To be used, m-THF passes methyl to Vitamin B12... 3. Vitamin B12 passes methyl to homocysteine...=methionine... 4. methionine distributes methyl groups to other compounds
Why is subacute combined degeneration of spinal cord seen in Vitamin B12 patients?
1. Vitamin B12 deficiency = increased Methylmalonic Acid... 2. Methylmalonic acid impairs spinal cord myelinzation
What is subacute combined degeneration, or Lictheim's disease?
1. degeneration of posterior and lateral columns of spinal cord... 2. associated with pernicious anemia... 3. weakness of legs, arms, trunk, tingling and numbness progressively worsenes... 4. mental state changes like reversible dementia, depression, etc.
What are the 5 defining changes that occur in megaloblastic anemia?
1. enlarged RBCs...macrocytosis 2. hypersegmented neutrophils and macroovalocytes (big oval shaped RBCs)... 3. rapidly dividing epithelial cells (i.e. intestine) 4. glossitis 5. decreased reticulocyte count
Where is intrinsic factor produced? What is the function of intrinsic factor?
1. gastric parietal cells... 2. bind to vitamin-B12 and facilitate absorption into ileum
What are the 5 laboratory findings of folate deficiency associated megaloblastic anemia?
1. macrocytic RBCs with hypersegmented neutrophils... 2. glossitis... 3. decreased serum folate levels... 4. increased homocysteine levels... 5. normal methylmalonic acid levels (negative finding)
(RX) What are the neurologic symptoms of patients with Vitamin B12 cobalamin deficiency?
1. reversible dementia...DEPRESSION 2. subacute degeneration of spinocerebellar tract, lateral corticospinal tract, dorsal column dysfunction...loss of VIBRATORY AND POSITION SENSE
(RX) What are the causes of vitamin B12 (cobalamin deficiency)?
1. veganism (insufficient take)... 2. malabsorption (Crohn disease)... 3. pernicious anemia... 4. Diphyllobothrium latum (fish tapeworm)... 5. gastrectomy
Vitamin B12 deficiency is the second cause, less common cause, of megaloblastic anemia. How is Vitamin B12 ordinarily absorbed?
1. vitamin B12 complexed to protein-derived sources (meat and eggs)... 2. Salivary gland secretes A. amylase to free B12... B. R-binder to bind B12... 3. Pancreatic proteases detach B12 from R-binder... in duodenum... 4. B12 binds to intrinsic factor (IF) from gastric parietal cells... 5. B12-IF complex absorbed in ileum
Why is methylmalonic acid increased in urine in vitamin B12 deficiency?
B12 is cofactor for methylmalonyl coa-mutase which converts methylmalonyl coa to succinyl coa... No cofactor then no conversion
Vitamin B12 deficiency megaloblastic anemia is less common than folate deficiency. How long does Vitamin B12 deficiency take to develop?
1. Years... 2. Large hepatic stores of Vitamin B12 cobalamin...
What are examples of nonmegaloblastic anemias?
1. alcohol consumption... 2. liver disease... 3. diamond black fan... 4. reticulocytosis 5. hypothyroidism
Poor diet leads to folate deficiency. What are 2 classic patient populations that have a poor diet, leading to folate deficiency?
1. alcoholics... 2. elderly
What are the features of non-megaloblastic macrocytic anemia?
1. MCV > 100 um^3... 2. no folate or vitamin B12 deficiency... 3. no megaloblastic changes in rapidly dividing cells nor hypersegmented neutrophils
Pernicious anemia is the most common cause of Vitamin B12 deficiency. Why?
1. Pernicious anemia is autoimmune destruction of parietal cells... 2. destroyed parietal cells = decreased Intrinsic Factor... 3. decreased intrinsic factor = reduced Vitamin B12 absorption in ileum
Why a methylmalonic acid levels normal in patients with folate deficiency-megaloblastic anemia? HIGH YIELD
1. Vitamin B12 helps to convert Methylmalonic Acid to Succinyl CoA... 2. In folate deficient patients, vitamin B12 levels are normal --> normal Methylmalonic Acid levels...
How can vitamin B12 deficient megaloblastic anemia be differentiated from folate deficient megaloblastic anemia on the differential?
1. Vitamin B12 helps to convert Methylmalonic Acid to Succinyl CoA... 2. In vitamin B12 deficient patients, vitamin B12 levels are low --> higher Methylmalonic Acid levels...
Why are vegans susceptible to Vitamin B12 deficiency?
1. Vitamin B12 is complexed with meat and eggs (protein-derived complexes)... 2. Vegans don't eat meat and eggs.
How do patients present with orotic aciduria?
1. failure to thrive (children)... 2. developmental delay... 3. megaloblastic anemia refractory to vitamin B12 or folate deficiency
What are the 5 main causes of megaloblastic macrocytic anemia?
1. folate deficiency... 2. vitamin B12 (cobalamin) deficiency... 3. orotic aciduria... 4. Drugs [Methotrexate, 5-FU, hydroxyurea]... 5. Zidovudine [HIV NRTIs]
Folate deficiency leads to megaloblastic anemia, a type of macrocytic anemia. How is folate obtained? Where is folate absorbed?
1. green vegetables and fruits (diet)... 2. jejunum (high yield)...
(RX) What are the lab findings in Folate deficiency?
1. increased homocysteine... 2. NORMAL MethylMalonic acid
(RX) What are the lab findings of vitamin B12 cobalamin deficiency?
1. increased homocysteine... 2. increased methylmalonic acid
What is glossitis? Why is glossitis a lab finding in folate deficiency megaloblastic anemia?
1. inflammation of tongue 2. no tongue cell turnover leads to accumulation and discomfort...
What are 4 symptoms of subacute combined degeneration?
1. loss of vibration... 2. loss of propioception... 3. spasticity... 4. weakness
What are the 5 laboratory findings of Vitamin B12 deficiency?
1. macrocytic RBCs with hypersegmented neutrophils... 2. glossitis... 3. Subacute combined degeneration of spinal cord... 4. decreased serum vitamin B12... 5. increased homocysteine levels... 6. increased methylmalonic acid levels
What 4 features do patients with Diamond-Black Fan anemia classically present with?
1. macrocytic anemia...nonmegaloblastic 2. upper limb malformations [triphalangeal thumbs]... 3. craniofacial abnormalities [flat nasal bridge]... 4. impaired growth/short stature
What are 2 types of macrocytic anemias?
1. megaloblastic... 2. non-megaloblastic
Folate antagonists lead to folate deficiency. What is 1 classic folate antagonists that leads to folate deficiency and how?
1. methotrexate... 2. methotrexate inhibits dihydrofluororeductase, inhibiting synthesis of folate into THF (bioavailabe form of folate)...
What are 3 drugs leading to folate deficiency?
1. methotrexate... 2. trimethoprim... 3. phenytoin
What is the etiology of Diamond-Black Fan anemia?
1. mutations of genes encoding ribosomal proteins RPS19... 2. RPS19 mutations induce aberrant p53 activity resulting in... 3. impaired erythropoeisis
Why are homocysteine levels increased in folate deficiency?
1. no folate = no methyl-THF... 2. no methyl-THF = no methyl transfer to Vitamin B12... 3. no m-B12 = no methyl transfer to homocysteine = no methionine... accumulation of homocysteine
Why are homocysteine levels increased in vitamin B12 deficiency?
1. no folate = no methyl-THF... 2. no methyl-THF = no methyl transfer to Vitamin B12... 3. no m-B12 = no methyl transfer to homocysteine = no methionine... accumulation of homocysteine
How can folate deficient megaloblastic anemia be differentiated from vitamin B12 deficient megaloblastic anemia on the differential?
1. normal methylmalonic acid levels... 2. Folate deficient patients have normal vitamin B12 levels... normal vitamin B12 levels = normal methylamalonic acid levels
How does orotic aciduria differ than ornithine transcarbamylase deficiency?
1. orotic aciduria: increased orotic acid NO hyperammonemia... 2. OTC deficiency: increased orotic acid WITH hyperammonemia
What are the 4 causes of Vitamin B12 deficiency? Which is the most common?
1. pernicious anemia (most common)... 2. pancreatic insufficiency... 3. damage to terminal ileum... 4. veganism diet...
What are the clinical findings in a patient with subacute combined degeneration of the spinal cord?
1. poor propioception and vibratory sensation (posterior column damage)... 2. spastic paresis (lateral corticospinal tract damage; weakness with muscle spasms, making walking difficult)
Increased demand for folate leads to folate deficiency. What are 3 patient populations that have increased demand for folate?
1. pregnant women (infant...dividing cells)... 2. cancer... 3. hemolytic anemias...
What autoimmune disease is strongly associated wtih pernicious anemia?
autoimmune atrophic gastritis... autoantibodies against hydrogen-potassium ATPases of gastric parietal cells are formed
What is megaloblastic anemia? What are two factors that lead to megaloblastic anemia?
macrocytic anemia (MCV > 100um^3) that is caused by... 1. folate deficiency... 2. vitamin B12 deficiency...
What are diagnostic features of pernicious anemia?
moderate to severe megaloblastic anemia... leukopenia with hypersegmented granulocytes.... neurological changes localized to posterolateral spinal tracts...spastic paraparesis (cramps, exaggerated reflexes, spasms making walking difficult) , sensory ataxia, parasthesisa lower limbs Methylmalonic acid in urine
What is the classic finding in patients with Diamond Black Fan anemia?
triphalangeal thumbs
How do you treat orotic aciduria?
uridine monophosphate bypass mutated enzyme
What patient is most likely to be susceptible to vitamin B12 deficiency?
vegans who strictly do not eat meats or eggs